Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Abstract

Gamma synuclein (SNCG) is a neuronal protein that is also aberrantly overexpressed in various types of human cancer. SNCG overexpression promotes cancer invasion and metastasis. However, the mechanisms that drive cancer metastasis upon SNCG expression remain elusive. Elucidation of the mechanisms underlying the promotion of cancer metastasis by SNCG may help discover therapeutic avenues for SNCG-overexpressed cancer. Here, we show that SNCG promotes transforming growth factor-β (TGF-β)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Mechanistically, SNCG promotes p38MAPK phosphorylation by interacting with the MAPK kinase 3/6 (MKK3/6) and prevents their degradation. SNCG knockdown leads to a decrease in TGF-β-induced phosphorylation of MKK3/6; and abrogates the induction of matrix metalloproteinase (MMP)-9 expression by TGF-β and its target gene Twist1. Furthermore, p38MAPK inhibition abrogates the promotion of MMP-9 expression and cancer cell invasion by SNCG. Both p38MAPK and MMP inhibitors can suppress the promotion of cancer cell invasion by SNCG. Finally, overexpression of SNCG in liver cancer cells promotes lung metastasis, which can be suppressed by the p38MAPK inhibitor. Together, our data uncover a previously unknown role of SNCG in promoting TGF-β-MKK3/6-p38MAPK signaling. This study highlights the critical role of p38MAPK in the promotion of cancer metastasis by SNCG, and indicates that p38MAPK inhibitor may serve as a potential therapeutic for SNCG-overexpressed cancer.

Dissecting gastric cancer heterogeneity and exploring therapeutic strategies using bulk and single-cell transcriptomic analysis and experimental validation of tumor microenvironment and metabolic interplay

“…SNCG, primarily expressed in neural tissues, is reported to upregulate in cancer tissues such as breast, ovary, colon, liver, and cervical cancer ( Liu et al, 2005 ). Like LOX, it has been primarily reported for regulating EMT to promote cancer metastasis ( Hsu et al, 2020 ; Liu et al, 2022 ). GFRA1, interacting with glial cell-derived neurotrophic factor (GDNF), promotes tumor progression ( Cavel et al, 2012 ; Ni et al, 2022 ).…”

Association of Parkinson’s Disease and Cancer: New Findings and Possible Mediators

“…‫-ץ‬Synuclein stimulates invasion and promotes metastasis in in vitro assays and animal models. In addition, ‫-ץ‬synuclein promotes phosphorylation of transforming growth factor-βinduced p38 mitogen-activated protein kinase (MAPK) phosphorylation [90]. These findings point to the essential role of p38MAPK promoting cancer metastasis by ‫-ץ‬synuclein and imply that p38MAPK inhibitors may serve as potential medications for ‫-ץ‬synuclein-overexpressed cancer [90].…”

Association between Parkinson’s Disease and Cancer: New Findings and Possible Mediators

“…Causes multinucleation and accelerated cell growth. Stimulates invasion; promotes metastasis [16] and, phosphorylation of TGF-β-induced p38 MAPK [17].…”